What are the side effects of Voriconazole (antifungal medication)?

From the Guidelines

Voriconazole is associated with several notable side effects, including visual disturbances, skin reactions, liver toxicity, neurological effects, QT interval prolongation, and an increased risk of skin cancers, emphasizing the need for careful monitoring and therapeutic drug monitoring to minimize toxicity and ensure effective treatment. The most common side effects of voriconazole include visual disturbances, such as blurred vision, altered color perception, and photophobia, which occur in about 30% of patients 1. These effects are typically temporary and resolve when the medication is stopped. Patients may also experience skin reactions, including photosensitivity that can cause severe sunburns with minimal sun exposure, requiring strict sun protection measures. Liver toxicity is another significant concern, necessitating regular monitoring of liver function tests during treatment. Neurological effects like hallucinations, confusion, and headaches can occur, particularly at higher blood levels. Voriconazole can also cause QT interval prolongation (affecting heart rhythm), nausea, vomiting, and rash. Long-term use has been associated with periostitis (bone pain) and an increased risk of skin cancers, especially squamous cell carcinoma. Some key points to consider when prescribing voriconazole include:

• Therapeutic drug monitoring is often recommended to maintain effective blood levels while minimizing toxicity, as voriconazole has variable metabolism between individuals 1.
• The target voriconazole trough values are between 0.5 and 4 mcg/mL for prophylaxis, while a higher range of 1 to 4 mcg/mL may be necessary for active disease and for patients with disease that has a poor prognosis 1.
• Voriconazole bioavailability is lowered by about 22% when taken with food and by 34% when given with a high-fat meal, so it should be given either 1 hour before or 1 hour after meals 1.
• Drug interactions are common as voriconazole affects the cytochrome P450 enzyme system, potentially altering the metabolism of many other medications, and patients should be closely monitored for signs of toxicity or reduced efficacy of concomitant medications 1.

From the FDA Drug Label

The most frequently reported adverse reactions (see Table 4) in the adult therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%).

Table 4 includes all adverse reactions which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of <2%

Dermatological reactions were common in patients treated with voriconazole. The mechanism underlying these dermatologic adverse events remains unknown Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported during treatment with voriconazole.

Less Common Adverse Reactions The following adverse reactions occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1655).

Voriconazole side effects include:

• Visual disturbances (18.7%): abnormal vision, color vision change, photophobia
• Gastrointestinal symptoms (5.4-5.7%): nausea, vomiting, fever
• Dermatological reactions (5.3%): rash, severe cutaneous adverse reactions (SCARs)
• Cardiovascular events (2.4%): tachycardia, hallucinations
• Hepatic events (2.7%): liver function test increased
• Other less common adverse reactions (<2%): abdominal pain, allergic reaction, anaphylactoid reaction, ascites, asthenia, back pain, etc. 2 2

From the Research

Voriconazole Side Effects

• Visual abnormalities (approximately 30%) 3
• Skin reactions (approximately 20%) 3
• Elevations in hepatic enzymes (< or =20%) 3
• Cutaneous malignancies, primarily squamous cell carcinoma (SCC) 4
• Phototoxicity 4
• Periostitis 4
• Hallucinations and encephalopathy 4
• Peripheral neuropathy 4
• Alopecia 4
• Nail changes 4
• Hyponatremia 4
• Hepatotoxicity in patients with severe liver dysfunction 5
• Changes in liver function tests (LFTs) during therapy, including elevated transaminases, cholestasis, or a combination of both 5

Risk Factors for Voriconazole Side Effects

• Initial loading dose greater than 300 mg (4.5 mg/kg) 5
• Severe liver dysfunction 5
• Pre-existing liver disease, diabetes, and hyperlipidemia 6
• High serum total bilirubin and creatinine levels 6

Management of Voriconazole Side Effects

• Dose reduction is recommended in patients with mild to moderate hepatic dysfunction (Child-Pugh class A or B) 3
• Lower doses and longer dosing intervals should be considered for patients with liver dysfunction 7
• Frequent monitoring of LFTs is recommended in patients with severe liver dysfunction 5
• Guidelines for screening for adverse effects after long-term voriconazole use may be beneficial and need to be established 4